Troxacitabine, an L-stereoisomeric nucleoside analog, on a five-times-daily schedule: A phase I and pharmacokinetic study in patients with advanced solid malignancies

Johann S. De Bono, Joseph Stephenson J., Sharyn D. Baker, Manuel Hidalgo, Amita Patnaik, Lisa A. Hammond, Geoffrey Weiss, Andrew Goetz, Lillian Siu, Cecelia Simmons, Jacques Jolivet, Eric K. Rowinsky

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Abstract

Purpose: To assess the feasibility of administering troxacitabine, a unique L-nucleoside that is not a substrate for deoxycytidine deaminase-mediated catabolism, as a 30-minute intravenous (IV) infusion daily for 5 days. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of troxacitabine as a 30-minute IV infusion daily for 5 days. Plasma and urine sampling was performed to characterize the pharmacokinetics and pharmacodynamics of troxacitabine. Results: Thirty-nine patients received 124 courses of troxacitabine at eight dose levels ranging from 0.12 to 1.8 mg/m2/d. Severe neutropenia that was protracted (> 5 days) and/or associated with fever, and skin rashes were consistently experienced by heavily (HP) and minimally pretreated (MP) patients at doses exceeding 1.2 and 1.5 mg/m2/d, respectively. At troxacitabine doses ≥ 1.2 mg/m2/d, treatment was often delayed 1 additional week for complete resolution of hematologic effects, resulting in lengthening of the treatment interval from every 3 to 4 weeks. Skin rash, palmar-plantar erythrodysesthesia, and thrombocytopenia were also observed and were occasionally severe, particularly at the highest doses. A patient with metastatic ocular melanoma experienced a partial response. Pharmacokinetics of troxacitabine were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance (Cs) were 60 (32) L and 161 (33) mL/min, respectively, on day 1. After treatment on the fifth day, terminal half-life values averaged 39 (63) hours, and Cs was reduced by approximately 20%, averaging 127 (27) mL/min. The principal mode of drug elimination was renal. Conclusion: Recommended doses for phase II studies of troxacitabine as a 30-minute infusion daily for 5 days every 4 weeks are 1.5 and 1.2 mg/m2/d for MP and HP patients, respectively. Broad disease-directed evaluations of troxacitabine on this schedule and possibly less frequent schedules are warranted.

Original languageEnglish (US)
Pages (from-to)96-109
Number of pages14
JournalJournal of Clinical Oncology
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    De Bono, J. S., Stephenson J., J., Baker, S. D., Hidalgo, M., Patnaik, A., Hammond, L. A., Weiss, G., Goetz, A., Siu, L., Simmons, C., Jolivet, J., & Rowinsky, E. K. (2002). Troxacitabine, an L-stereoisomeric nucleoside analog, on a five-times-daily schedule: A phase I and pharmacokinetic study in patients with advanced solid malignancies. Journal of Clinical Oncology, 20(1), 96-109. https://doi.org/10.1200/JCO.20.1.96